Developing strategies to identify individuals at risk for Parkinson disease (PD) and interventions to prevent its onset may be the best hope for reducing the disease burden. Preventative research has been limited by the relatively low incidence of PD, difficulties in defining samples at high risk for phenoconversion, and the lack of molecular targets for preventive treatments. The discovery that mutations in the leucine rich repeat kinase kinase (LRRK2) gene comprise the most common monogenic etiology of Parkinson disease (PD) provides an opportunity to address many of these challenges. The G2019S mutation accounts for up to 20% of PD in Ashkenazi Jews, and LRRK2 is considered a druggable target, making LRRK2 PD an important disease in its own right. LRRK2 PD also resembles idiopathic PD (IPD) in terms of clinical features, biomarkers, pathology and response to treatment, making it overall a model of great promise. To deliver on this promise, we must first better characterize the range of phenotypic expression in mutation carriers. Greater understanding of the phenotypic heterogeneity includes non-motor and early motor features. Non-motor abnormalities such as olfactory dysfunction, hyperechogenicity of the substantia nigra, and dysautonomia may occur before overt motor signs and clinical diagnosis of PD. These features, as well as non-skin cancer, have been reported in LRRK2 PD, however, their prevalence and predictive validity for manifesting PD is not known. Evaluation of a larger number of LRRK2 mutation PD subjects and carriers without PD will help determine whether non-motor abnormalities and non-skin cancer are mutation effects independent of development of PD (risk markers), or manifest in individuals who may be on the trajectory to motor worsening or have diagnosed PD (progression markers). Further, quantifying the presence and characteristics of non-motor and early motor PD features will illuminate human LRRK2 pathophysiology and help establish domains of disease burden. This proposal takes important steps towards defining the phenotype of LRRK2 G2019 in nonmanifesting carriers (NMC), as well as and in persons with established LRKK2 PD (MC), and will help pave the way for longitudinal study of LRRK2 NMC. This research builds on studies conducted during my K23 and capitalizes on two current studies funded by the Fox Foundation, the Consortium study of PD in Ashkenazi Jews (the Consortium, Beth Israel, Columbia, Tel Aviv), and a DaTSCAN study in a subset of first degree relatives of LRRK2 PD Consortium subjects (the Institute for Neurodegenerative Disease, IND study). It will critically expand both studies by adding measures to both New York and Israeli sites (Aim 1), including cancer assessment (Aim 3), and combining Consortium marker data with a surrogate marker for dopaminergic dysfunction (Aim 2). This research, together with a program of structured training in genetics, epidemiology and transcranial sonography will help me develop as a Parkinson disease (PD) researcher who will facilitate the development, testing and early application of Parkinson therapeutics through better characterization of the disease, and understanding markers of parkinsonism. I have extensive training in movement disorders and epidemiology, and have published on LRRK2 PD, Gaucher associated PD, and biomarkers associated with PD, particularly spiral analysis and transcranial sonography. The proposed educational plan in the K02 would allow me to deepen my knowledge and expertise in the areas of genetics, epigenetics, and imaging with transcranial sonography, and epidemiology through coursework, practical training and the research study. As noted, this study will expand on a large Consortium study of a unique cohort of Ashkenazi Jews with PD, family members and controls, by adding measures and new analyses. In Aim 1 candidate non-motor, quantitative motor and imaging measures will be compared between different subgroups of mutation carriers, PD without LRRK2 G2019S mutation, and controls. In Aim 3, the association between non-skin cancer and LRRK2 PD will be tested. Finally in Aim 2, DAT scan will be used as a surrogate outcome marker for development of PD, as progression cannot be directly studied in cross-section. Longitudinal analysis of progression of non-motor features in the planned R01 as a direct outgrowth of this study will allow determination of A) an algorithm of markers which predicts phenoconversion, and B) the slopes of marker progression relative to the onset of PD, and the determination of an intermediary state which is present prior to manifesting PD. PUBLIC HEALTH RELEVANCE: Mutations in the LRRK2 gene constitute the leading genetic model for Parkinson's disease. However, much is not yet known about the clinical course of Parkinson's disease in mutation carriers, whether non-motor features are present prior to the development of PD, and whether these correlate with pathologic brain changes. This study capitalizes on an existing precious cohort of LRRK2 PD, other PD and family members in order to better learn about these features.